Obstructive Sleep Apnea Causes Widespread Gene Disruption in Mice throughout the Day

The results of a study in a mouse model of obstructive sleep apnea (OSA) suggest that the low blood oxygen levels (hypoxia) caused by the condition can lead to widespread changes in gene activity in different tissues throughout the day. Findings from the study, carried out by Cincinnati Children’s Hospital Medical Center scientists and their colleagues, indicated that transcriptomic changes in cardiopulmonary tissues were more affected by the resulting intermittent hypoxia (IH) than were other tissues. The overall study results could lead to the development of tools for earlier diagnosis and tracking of OSA, the team suggested.

The effects of sleep apnoea on mouse gene expression
Obstructive sleep apnea disrupts gene activity throughout the day in mice. Created with biorender.com. [Bala S. C. Koritala (CC-BY 4.0, https://creativecommons.org/licenses/by/4.0/)]
Headed by David Smith, PhD, the researchers reported on their results in PLOS Biology, in a paper titled “Obstructive sleep apnea in a mouse model is associated with tissue-specific transcriptomic changes in circadian rhythmicity and mean 24-hour gene expression.” In their paper they concluded “In summary, our findings demonstrate a unique relationship between early exposure to IH and distinct changes in biological pathways that contribute to physiological outcomes … Our findings provide novel insight into the pathophysiological mechanisms that could be associated with end-organ damage in patients with chronic exposure to IH.”

Obstructive sleep apnea occurs when the airway becomes blocked (usually by soft tissue, associated with snoring and interrupted breathing during the night), resulting in intermittent hypoxia, or low blood oxygen, and disrupted sleep. The authors cited figures indicating that the condition affects over one billion people worldwide, and costs $150 billion per year in direct medical costs in the U.S. alone. The IH linked to OSA increases the risk for cardiovascular, respiratory, metabolic, and neurologic complications.

In patients with OSA, IH occurs only during the sleep phase of the 24-hour sleep–wake cycle, and this has the potential to alter physiological circadian rhythms, the authors explained. “The circadian clock is a molecular oscillator that uses positive and negative transcriptional–translational feedback loops of the core clock components … Circadian clocks are one of the key components in maintaining systemic homeostasis since they act as timekeepers for molecules, cells, organs, and physiological processes.”

The activity of many genes varies naturally throughout the day, partially in response to activity of circadian clock genes, whose regular oscillations drive circadian variation in up to half the genome. However, the investigators noted, “the circadian clock can be disrupted by internal factors (e.g., health conditions) and external factors (e.g., living conditions).” External factors that can impact on gene activity include decreases in oxygen levels, which causes production of hypoxia-inducible factors that influence the activity of many genes, including clock genes.

To better understand how OSA may affect gene activity throughout the day the authors exposed mice to intermittent hypoxic conditions and examined whole-genome transcription in six tissues—lung, liver, kidney, muscle, heart, and cerebellum—throughout the day. The authors then evaluated variation in the circadian timing of gene expression in these same tissues. “Since chronic, untreated OSA is primarily associated with negative cardiopulmonary outcomes, we hypothesized that IH would impact the biological processes of lung and heart more rapidly than other tissues,” they commented.

The results did show that the largest changes were in the lung, where intermittent hypoxia affected the transcription of almost 16% of all genes, most of which were upregulated. Just under 5% of genes were affected in heart, liver, and cerebellum. The subset of genes that normally exhibit circadian rhythmicity were even more strongly affected by intermittent hypoxia, with significant changes seen in 74% of such genes in the lung and 66.9% of such genes in the heart. Among the genes affected in each tissue were known clock genes, an effect that likely contributed to the large changes in circadian activity of other genes seen in these tissues. The team then used the transcriptomic changes to examine altered biological processes and physiological changes in mammals. “The results suggest that the transcriptome of cardiopulmonary tissues and associated biological processes were more impacted in comparison with other evaluated tissues,” they noted. “Our findings demonstrate a relationship between early exposure to IH and changes in specific physiological outcomes.”

Co-author Bala S. C. Koritala, PhD, stated, “Our study using an animal model of obstructive sleep apnea unveils time- and tissue-specific variations of the whole genome transcriptome and associated hallmark pathways. These unique findings uncover early biological changes linked to this disorder, occurring across multiple organ systems.”

They noted that “A key challenge to preventive care in patients with OSA is “early diagnosis” prior to the development of associated medical comorbidities.” The data from their newly reported study, they suggest,  provide insights into the early changes in relevant biological pathways. “Our findings suggest that there is time- and tissue-specific variability of the whole-genome transcriptome in multiple organ systems following even a short exposure to IH, with the lung transcriptome being the most affected in comparison with other organs.”

Smith added, “Our findings provide novel insight into the pathophysiological mechanisms that could be associated with end-organ damage in patients with chronic exposure to intermittent hypoxia, and may be useful to identify targets for future mechanistic studies evaluating diagnostic or therapeutic approaches;” for instance, through a blood test tracking one of the dysregulated gene products to detect early OSA.